Among the different routes of drug administration that have been investigated to release a bioactive agent, for instance a pharmacologically active agent, in a controlled way, the oral route has by far received the most attention. Such controlled release implies a system that provides continuous delivery of the active ingredient for a predetermined period of time with predictable and reproducible kinetics and preferably with a known mechanism of action. In addition, the dosage form must enable drug release in a specific area within the gastro-intestinal tract for systemic or local action.
Controlled release by modification of the dosage form relies on different physicochemical principles such as dissolution, diffusion, osmotic pressure. Muco-adhesion is still less frequently used, whereas ion-exchange has become almost obsolete.
Although today many controlled release preparations are approved and marketed, there is still need to optimise controlled release dosage forms to improve drug convenience, to boost efficacy or to reduce toxicity or side effects. Indeed, the currently available technology lacks flexibility to adapt existing controlled release drug products to the needs of certain populations of patients like elderly or children. Moreover improved controlled release oral delivery systems can induce a switch from injections to oral uptake forms for several drugs, which currently have to be administered parenterally. For certain medicaments drug convenience can also considerably be improved by reducing the amount of pills or tablets that have to be swallowed daily. In addition, undesirable dose dumping with reservoir systems or initial burst effects in the available monolithic matrix type dosage forms are still encountered.
Several types of silica based drug delivery systems have been investigated in view of optimising controlled drug delivery. The silica in these formulations can either act as a porous reservoir from which the therapeutic compound eludes through diffusion. In other formulations the silica is present in a bio-erodible form. Bio-erosion refers to a gradual disintegration of the silica microstructure after administration which facilitates the delivery of the bioactive compound. Bio-erodible formulations are mostly based on silica-drug composite xerogels or fibres.
Amorphous and paracrystalline materials represent an important class of porous inorganic solids that have been used for many years in industrial applications. Typical examples of these materials are the amorphous silicas commonly used in catalyst formulations and the paracrystalline transitional aluminas used as solid acid catalysts and petroleum reforming catalyst supports. The term “amorphous” is used herein to indicate a material with no long range order. An alternate term that has been used to describe these materials is “X-ray indifferent”. For example, the microstructures of silica gels consist of 10-25 nm particles of dense amorphous silica, with porosity resulting from voids between the particles. Since there is no long range order in these materials, the pore sizes tend to be distributed over a rather wide range. This lack of order also manifests itself in the X-ray diffraction pattern, which is usually featureless.
Paracrystalline materials such as the transitional aluminas also have a wide distribution of pore sizes, but better defined X-ray diffraction patterns usually consisting of a few broad peaks. The microstructure of these materials consists of tiny crystalline regions of condensed alumina phases and the porosity of the materials results from irregular voids between these regions. Since, in the case of either material, there is no long range order controlling the sizes of pores in the material, the variability in pore size is typically quite high. The pore sizes in these materials is from about 1.3 nm to about 20 nm.
In sharp contrast to these structurally ill-defined solids are materials whose pore size distribution is very narrow because it is controlled by the precisely repeating crystalline nature of the materials' microstructure. These materials are called “molecular sieves”, the most important examples of which are zeolites.
Zeolites, both natural and synthetic, have been demonstrated in the past to have catalytic properties for various types of hydrocarbon conversion. Certain zeolitic materials are ordered, porous crystalline aluminosilicates having a definite crystalline structure as determined by X-ray diffraction, within which there are a large number of smaller cavities which may be interconnected by a number of still smaller channels or windows. These cavities and pores are uniform in size within a specific zeolite material. Since the dimensions of these pores are such as to accept for adsorption molecules of certain dimensions while rejecting those of larger dimensions, these materials are known as “molecular sieves” and are utilized in a variety of ways to take advantage of these properties.
Such molecular sieves, both natural and synthetic, include a wide variety of positive ion-containing, crystalline silicates. These silicates can be described as a rigid three-dimensional framework of SiO4 and Periodic Table Group IIIB element oxide, e.g. AlO4, in which tetrahedra are crosslinked by the sharing of oxygen atoms whereby the ratio of the total Group IIIB and Group IVB, e.g. silicon, atoms to oxygen atoms is 1:2. Crystalline microporous silicon dioxide polymorphs represent compositional end members of these compositional material families. These silica molecular sieves do not have cation exchange capacity.
Generally, porous substances are divided by pore size, for example, pore sizes smaller than 2 nm classified as microporous substances, between 2 and 50 nm classified as mesoporous substances and larger than 50 nm classified as macroporous substances. Micropores are conveniently subdivided into ultramicropores narrower than 1.5 nm, and supermicropores with free diameters from 1.5 to 2 nm. Of the porous substances, those having uniform channels, such as zeolite, are defined as molecular sieves. Up to hundreds of types of species have been found and synthesised thus far. Zeolites play an important role as catalysts or carriers in modern chemical industries by virtue of their characteristics including selective absorptivity, acidity and ion exchangeability. However, the molecular size of a reactant which can be utilized in catalyst conversion reactions, etc. is limited by the pore size of zeolite because zeolite is an ultramicroporous molecular sieve. For example, when ZSM-5 zeolite is applied in a catalytic cracking reaction, its reactivity becomes significantly decreased as the reactant changes from n-alkane to cycloalkane and further to branched alkane. Hence, an enormous effort has been made all over the world to synthesize molecular sieves having larger pores than that of zeolite. As a result, AlPO4, VPI-5, Cloverlite and JDF-20 having larger micropore size than that of traditional zeolites were developed. However, with those molecular sieves ultramicroporous size limit cannot be exceeded.
Among solid substances known thus far, those having uniform channels, such as zeolites represented by porous crystalline aluminium silicates and porous crystalline aluminum phosphates (AlPO4) are defined as molecular sieves, because they selectively adsorb molecules smaller than the size of the channel entrance or they allow molecules to pass through the channel. In view of crystallography, zeolites are fully crystalline substances, in which atoms and channels are arranged in complete regularity. These fully crystalline molecular sieves are obtained naturally or synthesized through hydrothermal reactions. The number of fully crystalline molecular sieves obtained or synthesized thus far amounts to several hundreds of species. They play an important role as catalysts or supports in modern chemical industries by virtue of their characteristics including selective adsorption, acidity and ion exchangeability. Examplary current catalytic processes using the characteristics of zeolite include a petroleum cracking reaction using ZSM-5 and an aromatic conversion reaction of paraffin using KL-zeolite impregnated with platinum. A significant problem of the fully crystalline molecular sieves is that the active sites in the crystal interior are not accessible to molecules larger than about 1.3 nm in size.
A series of ordered mesoporous materials, including MCM-41 and MCM-48, was reported in U.S. Pat. Nos. 5,057,296 and 5,102,643. These ordered materials show a structure in which mesopores uniform in size are arranged regularly. MCM-41, has a uniform structure exhibiting hexagonal arrangement of straight mesopores, such as honeycomb, and has a specific surface area of about 1,000 m2/g as measured by ordinary BET.
Existing molecular sieves have been produced by using inorganic or organic cations as templates, whereas those ordered mesoporous materials are synthesized through a liquid crystal template pathway by using surfactants as templates. These ordered mesoporous materials have the advantage that their pore sizes can be adjusted in a range of 1.6 to 10 nm by controlling the kinds of surfactants or synthesis conditions employed during the production process.
Ordered mesoporous materials designated as SBA-1, -2 and 3 were reported in Science (1995) 268:1324. Their channels are regularly arranged, while the constituent atoms show an arrangement similar to that of amorphous silica. Ordered mesoporous materials have regularly arranged channels larger than those of existing zeolites, thus enabling their application to adsorption, isolation or catalytic conversion reactions of relatively large molecules.
U.S. Pat. No. 6,592,764 discloses a family of high quality, hydro-thermally stable and ultra large pore size mesoporous silica by using amphiphilic block copolymers in acidic media. One member of the family, SBA-15, has a highly ordered, two-dimensional hexagonal honeycomb, hexagonal cage or cubic cage mesostructure. Calcination at 500° C. yields porous structures with high BET surface areas of 690 to 1,040 m2/g, and pore volumes up to 2.5 cm3/g, ultra large d(100) spacings of 7.45-45 nm, pore sizes from 4.6-50 nm and silica wall thicknesses of 3.1-6.4 nm. SBA-15 can be readily prepared over a wide range of specific pore sizes and pore wall thicknesses at low temperature (35-80° C.) using a variety of commercially available, non-toxic and biodegradable amphiphilic block copolymers, including triblock polyoxyalkylenes. U.S. Pat. No. 6,592,764 does not suggest use of such materials in drug delivery.
U.S. Pat. No. 6,630,170 discloses a mesoporous composition prepared from a mixture comprising hydrochloric acid, vitamin E and a silica source, wherein said vitamin E functions as a templating molecule, and said mesoporous composition exhibits uniform pore size. U.S. Pat. No. 6,630,170 suggests using such a composition as a drug delivery vehicle for water-insoluble drugs, however it does not show any drug release profile.
U.S. Pat. No. 6,669,924 discloses a mesoporous zeolitic material having a stereoregular arrangement of uniformly-sized mesopores with diameters ranging from 2 to 50 nm and walls having a thickness of at least 4 nm and a microporous nanocrystalline structure, the mesopore walls having a stereoregular arrangement of uniformly-sized micropores with diameters less than 1.5 nm. U.S. Pat. No. 6,669,924 does not suggest use of such materials in drug delivery.
WO 2005/000740 discloses ordered mesoporous silica materials such as Zeotile-4 being obtained by assembly of nanometer size building units having zeolite framework, said silica materials having two or more levels of porosity and structural order, and wherein the internal structure of said nanometer size building units does not give rise to Bragg type diffraction in a powder X-ray diffraction pattern of said crystalline mesoporous silica material. FIG. 5 of WO 2005/000740 shows a very fast drug release (63% after 10 minutes) obtained by dispersing 20% itraconazole into 80% Zeotile-4.
The use of siliceous zeolites and ordered mesoporous silica materials for drug delivery applications has emerged as a promising technology in the past few years. The combination of purified natural zeolites with drugs has been investigated. It was demonstrated that such zeolites do not degrade drug molecules, have good stability during passage through the stomach and do not produce biological damage to humans.
Compared to zeolites, ordered mesoporous materials such as MCM-41 have wider pores with diameters exceeding 2 nm and larger pore volumes. The open porosity of such materials makes them suitable as potential matrices for adsorption and subsequent delayed release of a variety of molecules having therapeutic activity such as ibuprofen.
Several sol-gel processed drug-silica composite materials have been investigated for controlled drug release. One concept involving the use of sol-gel type silica is the synthesis of a bio-erodible silica-drug composite. Toremifene citrate and dexmedetomidine hydrochloride were encapsulated in silica particles using a polymerisation process starting from tetraethyl-orthosilicate (hereinafter referred as TEOS) in presence of the drug substance (Kortesuo et al., Biomaterials 21 (2000) 193-198; Ahola et al., Int. J. Pharm. 195 (2000) 219-227; Kortesuo et al., Int. J. Pharm. 200 (2000) 223-229). Sol-gel type silica synthesized in presence of protein medicines was also used as a bio-erodible carrier material for the controlled release of proteins such as trypsin inhibitor (Santos et al., Biomaterials 20 (1999) 1695-1700) and the mucopolysaccharide heparin (Ahola et al., Biomaterials 22 (2001) 2163-2170). In these silica-based drug release systems prepared using sol-gel approaches, the drug molecules are introduced during polymerisation and processing of the silica matrix. Polymerisation is performed under relatively mild conditions of pH in order not to modify the drug compound. Release of the drug molecules from these drug-silica composite materials occurs via a combination of bio-erosion and pore diffusion mechanisms.
An alternative approach for making a drug delivery system based on silica gels is the synthesis of silica in the absence of the medicinal compound, followed by drying and calcination to obtain a xerogel and then by loading the calcined material with the appropriate drug.
The sol-gel approach enables the synthesis of a large variety of silica materials. The texture and properties of sol-gel processed silica materials prepared by the hydrolysis and condensation of TEOS are dependent upon chemical composition, temperature and pH during gel formation, and drying conditions. Especially, the connectivity of the silicate network and the porosity are dependent upon the water/alkoxide ratio and upon the nature of the catalyst used for hydrolysis and condensation. The molar ratio r=water/alkoxide, commonly referred to as the molar hydrolysis ratio, determines the sequence of hydrolysis and polymerisation reactions. At r values exceeding 10, hydrolysis and condensation reactions occur in consecutive steps. In alkaline media, spherical silica sol particles are formed which finally form the network of the gel at the sol-gel transition point. Under basic conditions, branched silicate chains and spherical sol particles are preferred, which can be converted into gels which develop into mesoporous matrices with uniform cylindrical pores by Ostwald ripening process. At lower r values, hydrolysis and condensation proceed simultaneously. Linear growth of the silicate polymer is favored in strongly acidic media. Under conditions with shortage of water (low r value), the silicate particles contain residual alkoxy groups. By careful removal of these residual organic groups through calcination, micropores with very narrow pore size distribution can be obtained.
In the field of drug release systems, hitherto acid catalyzed silica polymerisation at low r values has only be used to incorporate the drug substance during the silica polymerisation process itself. In such applications, mildly acidic conditions must be used in order to avoid deterioration of the drug substance and to obtain a non aggressive drug delivery system because the acid cannot be removed from the formulation before use.
In Adv. Mater. (1993) 5:726-730, Maier et al. reported the synthesis of microporous amorphous oxides useful for the preparation of microporous membranes capable of molecular size exclusion. Using a sol-gel technique starting with the polymerization of tetraethoxysilane (TEOS) under acidic conditions (highly concentrated hydrochloric acid) and a molar hydrolysis ratio (r value) of 1 explained the formation of a gel instead of a fibrous material. Maier et al. used a HCl/TEOS molar ratio of 0.30, followed by calcination of the silica gel and evacuation of the occluded alkoxy groups. In particular a microporous silica was obtained with a pore diameter maximum of 0.6 nm, a BET surface area of 800 m2/g and a micropore volume of 0.25 cm3/g. Microporous titania, zirconia and alumina with a narrow monomodal pore-size distribution and a pore size maximum below 1 nm were prepared by Maier et al. using similar procedures.
EP-A-812,305 discloses microporous amorphous, non-ceramic glasses consisting of a matrix of mixed metal oxides, in which about 90% of the pores of the material have an effective diameter from 0.3 to 1.2 nm and essentially the same pore size and a surface area of more than 50 m2/g, which are useful in heterogeneous catalysis, e.g. for inducing oxidation, hydrogenation, hydro-cracking and condensation. Similar microporous silica materials are described in EP-A-590,714, namely bifunctional catalysts consisting of amorphous silica-alumina gel as determined by X-ray diffraction and one or more metals belonging to Group VIIIA for use in the catalytic conversion of hydro-isomerisation of paraffins. EP-A-876,215 also discloses microporous amorphous mixed oxides having, in dried form, a narrow pore size distribution, micropores with diameters below 3 nm and a total surface area from 20 to 1,000 m2/g and containing a fraction of from 0.1 to 20% by weight of non-hydrolyzable organic groups. However neither Maier et al. nor any of the latter patents teaches the use of such materials in drug delivery.
According to Radin et al. in Biomaterials (2002) 15:3113-22, room-temperature processed silica-based sol-gel, termed silica xerogels, are porous, degradable materials that can release biologically functional molecules in a controlled manner. According to Barbéet al. in Advanced Materials (2004) 16:1959-1966, the diffusion of molecules inside a microporous solid is much slower than inside a mesoporous gel. This leads to significantly smaller release rates for the gels synthesized using acid catalysis than for those synthesized using basic conditions.
As evidenced by the prior art discussed herein-above, there is still a need in the art for drug delivery systems with specifically controlled release rates, in particular slow or delayed or prolonged release rates, based on silicon oxide materials. There is also a need in the art for such drug delivery systems wherein the silicon oxide material with specific porosity can be produced in the absence of the drug and can be loaded with the drug afterwards within a wide range of drug loadings.